Cerebrovascular disease is one of the leading causes of death in the USA, with more than 140,000 people dying each year from a stroke. While age remains the greatest risk factor for stroke, other conditions are also known to predispose individuals, including hypertension, obesity, diabetes and sickle cell disease (SCD). SCD in particular renders both adults and children vulnerable to ischemic stroke (e.g. 24% of SCD patients have a clinically apparent stroke by the age of 45 and 11% by the age of 20) and silent cerebral infarction ([SCI] which whilst quantifiable by MRI, produces no focal neurologic signs). It is therefore not surprising that SCD is frequently referred to as a ?hypercoagulable state? characterized by a proinflammatory and prothrombogenic phenotype. Whilst the molecular origin of SCD is clear, the mechanisms that contribute to the prothrombogenic phenotype have not been fully elucidated. It is known that circulating neutrophils of SCD patients are activated and as such this has provided indirect evidence for their implication in thrombosis and vasoocclusive crises that accompany this condition. However, the actual role that neutrophils play and how they contribute directly to thrombus formation, especially in the brain, is currently unknown. We believe that by understanding the ways that neutrophils contribute not only to the systemic prothrombogenic phenotype of SCD, but more specifically to the actual local thrombosis, we will uncover the potential of targeting neutrophils as a therapeutic strategy for this debilitating and life threatening disease.
Sickle cell disease (SCD) is a chronic, genetic disease resulting from a single amino acid substitution in the hemoglobin ? chain of red blood cells, which affects millions of people worldwide. SCD patients suffer from a prothrombogenic phenotype with excess clot formation and thrombosis, leading to serious consequences such as ischemic stroke. Markers of neutrophil activity have revealed that circulating neutrophils of SCD patients are activated and as such this has provided indirect evidence for their implication in thrombosis. In the proposed studies we will investigate ways in which neutrophils contribute directly to cerebral thrombosis, something that is currently unknown and has never been investigated. We strongly believe that by understanding ways that neutrophils contribute not only to the systemic prothrombogenic phenotype of SCD, but more specifically to the actual local thrombus formation, we will uncover the potential implication of targeting neutrophils as a therapeutic strategy for this debilitating and life threatening disease.
